Iron imaging reveals tumor and metastasis macrophage hemosiderin deposits in breast cancer.

Iron-deposition is a metabolic biomarker of macrophages in both normal and pathological situations, but the presence of iron in tumor and metastasis-associated macrophages is not known. Here we mapped and quantified hemosiderin-laden macrophage (HLM) deposits in murine models of metastatic breast cancer using iron and macrophage histology, and in vivo MRI. Iron MRI detected high-iron pixel clusters in mammary tumors, lung metastasis, and brain metastasis as well as liver and spleen tissue known to contain the HLMs. Iron histology showed these regions to contain clustered macrophages identified by their common iron status and tissue-intrinsic association with other phenotypic macrophage markers. The in vivo MRI and ex vivo histological images were further processed to determine the frequencies and sizes of the iron deposits, and measure the number of HLMs in each deposit to estimate the in vivo MRI sensitivity for these cells. Hemosiderin accumulation is a macrophage biomarker and intrinsic contrast source for cellular MRI associated with the innate function of macrophages in iron metabolism systemically, and in metastatic cancer

Familial Mediterranean Fever and Hypercoagulability

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like skin disease. As such, FMF is a prototype of autoinflammatory diseases where genetic changes lead to acute inflammatory episodes. Systemic inflammation – in general - may increase procoagulant factors, and decrease natural anticoagulants and fibrinolytic activity. Therefore, it is anticipated to see more thrombotic events among FMF patients compared with healthy subjects. However, reviewing the current available literature and based upon our personal experience, thrombotic events related purely to FMF are very rare. Possible explanation for this discrepancy is that along with the procoagulant activity during FMF acute attacks, anticoagulant and fibrinolytic changes are also taking place. Colchicine which is the treatment of choice in FMF may also play a role in reducing inflammation thereby decreasing hypercoagulability

Glucocorticoid sensitivity in Behcet's disease

WOS: 000209773300007PubMed ID: 23781311Objective: Glucocorticoid (GC) sensitivity is highly variable among individuals and has been associated with susceptibility to develop (auto-) inflammatory disorders. The purpose of the study was to assess GC sensitivity in Behcet's disease (BD) by studying the distribution of four GC receptor (GR) gene polymorphisms and by measuring in vitro cellular GC sensitivity. Methods: Healthy controls and patients with BD in three independent cohorts were genotyped for four functional GR gene polymorphisms. To gain insight into functional differences in in vitro GC sensitivity, 19 patients with BD were studied using two bioassays and a whole-cell dexamethasone-binding assay. Finally, mRNA expression levels of GR splice variants (GR-alpha and GR-beta) were measured. Results: Healthy controls and BD patients in the three separate cohorts had similar distributions of the four GR polymorphisms. The Bcll and 9 beta minor alleles frequency differed significantly between Caucasians and Mideast and Turkish individuals. At the functional level, a decreased in vitro cellular GC sensitivity was observed. GR number in peripheral blood mononuclear cells was higher in BD compared with controls. The ratio of GR-alpha/GR-beta mRNA expression levels was significantly lower in BD. Conclusions: Polymorphisms in the GR gene are not associated with susceptibility to BD. However, in vitro cellular GC sensitivity is decreased in BD, possibly mediated by a relative higher expression of the dominant negative GR-b splice variant. This decreased in vitro GC sensitivity might play an as yet unidentified role in the pathophysiology of BD.The Dutch Arthritis AssociationThis work was supported by a grant from The Dutch Arthritis Association

Routine germline <i>BRCA1</i> and <i>BRCA2 </i>testing in ovarian carcinoma patients:analysis of the Scottish real life experience

Objective: To determine the rate of germline BRCA1 and BRCA2 mutations in Scottish ovarian cancer patients before and after a change in testing policy. Design: Retrospective cohort study. Setting: Four cancer/genetics centres in Scotland. Population: Ovarian cancer patients undergoing germline BRCA1 and BRCA2 (gBRCA1/2) gene sequencing before 2013 (‘old criteria’; selection based solely on family history), after 2013 (‘new criteria’; sequencing offered to newly presenting non-mucinous ovarian cancer patients) and the ‘prevalent population’ (who presented before 2013, were not eligible for sequencing under the old criteria but were sequenced under the new criteria). Methods: Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria. Main Outcome Measures: Frequency of germline BRCA1, BRCA2, RAD51C and RAD51D mutations. Results: Of 599 patients sequenced, 205, 236 and 158 were in the ‘old criteria’, ‘new criteria’ and ‘prevalent’ populations respectively. The frequency of gBRCA1/2 mutations was 30.7%, 13.1% and 12.7% respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. 48% (15/31) ‘new criteria’ patients with gBRCA1/2 mutations had a Manchester score &#60;15 and would not have been offered sequencing based on family history criteria. In addition, 20 gBRCA1/2 patients were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients &#62;70 years was 8.2%. Conclusions Sequencing all non-mucinous ovarian cancer patients produces much higher annual gBRCA1/2 mutation detection with the frequency of positive tests still exceeding the 10% threshold upon which many family history based models operate

Imaging endogenous macrophage iron deposits reveals a metabolic biomarker of polarized tumor macrophage infiltration and response to CSF1R breast cancer immunotherapy.

Iron deposits are a phenotypic trait of tumor-associated macrophages (TAMs). Histological iron imaging and contrast-agent free magnetic resonance imaging (MRI) can detect these deposits, but their presence  in human cancer, and correlation with immunotherapeutic response is largely untested. Here, primarily using these iron imaging approaches, we evaluated the spatial distribution of polarized macrophage populations containing high endogenous levels of iron in preclinical murine models and human breast cancer, and used them as metabolic biomarkers to correlate TAM infiltration with response to immunotherapy in preclinical trials. Macrophage-targeted inhibition of the colony stimulating factor 1 receptor (CSF1R) by immunotherapy was confirmed to inhibit macrophage accumulation and slow mammary tumor growth in mouse models while also reducing hemosiderin iron-laden TAM accumulation as measured by both iron histology and in vivo iron MRI (FeMRI). Spatial profiling of TAM iron deposit infiltration defined regions of maximal accumulation and response to the CSF1R inhibitor, and revealed differences between microenvironments of human cancer according to levels of polarized macrophage iron accumulation in stromal margins. We therefore demonstrate that iron deposition serves as an endogenous metabolic imaging biomarker of TAM infiltration in breast cancer that has high translational potential for evaluation of immunotherapeutic response

Two Cases of Acute Leukopenia Induced by Colchicine with Concurrent Immunosuppressants Use in Behçet's Disease

Colchicine-induced leukopenia usually occurrs in intentional or accidental overdoses or inappropriate use in combination with intravenous and oral colchine; however, there have been several reports of hematologic toxicity in short-term and small-dose colchicine medication courses. We present two cases of leukopenia induced by colchicine use concurrent with immunosuppressants in Behçet's disease. We postulate that the mechanism of colchicine-induced leukopenia might be the destruction of circulating leukocytes and an inhibition of leukocyte production by the immediate and direct toxic effect of colchicine on idiosyncrasies unique to each patient. The concurrently administered immunosuppressant might decrease the threshold for hematologic toxicity of colchicine in the leukocytes and their precursor cells

Mitral Stenosis Presenting with Acute Hearing Loss

A 47-year old woman presented with acute hearing loss, followed by dyspnea and then reduced consciousness and a hemiparesis. Investigations led to a diagnosis of cardiac emboli related to rheumatic mitral stenosis

Prosthetic valve endocarditis due to Streptococcus pneumoniae

Abstract Introduction In the pre-antibiotic era up 10% of cases of infective endocarditis were due to Streptococcus pneumoniae, but this association is currently exceedingly rare. Case description Since 1997 we have diagnosed three patients, all aged &gt;70, with endocarditis due to S. pneumoniae. One of these three cases involved a prosthetic valve, another a prosthetic ring. All three patients completely recovered with antibiotic treatment only. Discussion and evaluation During the same period there were 1694 cases of pneumococcal bacteremia, of whom 395 (23%) after age 70. Therefore, after age 70 the prevalence of endocarditis out of all cases of pneumococcal bacteremia was 0.7%. A literature review detected another 16 cases of pneumococcal PVE. The mean age of these 17 patients was 64±14; 10 were female and 7 male. In most instances, symptom duration was short, &lt; 6 days. Valve surgery was performed in 5 cases (29%) and 13 patients (76%) survived. Conclusions Endocarditis due to S. pneumoniae is rare in the antibiotic era; even in patients with prosthetic valves its course is evidently not more virulent than with other low-virulent organisms. </jats:sec